On the synthesis of β-bromohydrine ethers via intermolecular alkoxyl radical addition to bicyclo[2.2.1]heptene

Article abstract of DOI:10.1016/j.tetlet.2007.06.103

Primary, secondary, and tertiary alkoxyl radicals add exo-selectively to the olefinic π-bond in bicyclo[2.2.1]heptene to afford exo-2-alkoxybicyclo[2.2.1]hept-3-yl radicals, which are trapped with BrCCl₃ preferentially from the endo face to furnish β-bromohydrine ethers in 23-67% yield.

Full text of DOI:10.1016/j.tetlet.2007.06.103

Tetrahedron Letters 48 (2007) 6027–6030
On the synthesis of b-bromohydrine ethers via intermolecular
alkoxyl radical addition to bicyclo[2.2.1]heptene
Jens Hartung,* Nina Schneiders and Thomas Gottwald
Fachbereich Chemie, Organische Chemie, Technische Universita¨t Kaiserslautern, Erwin-Schro¨dinger-Straße,
D-67663 Kaiserslautern, Germany
Received 2 April 2007; revised 11 June 2007; accepted 18 June 2007
Available online 24 June 2007
Abstract—Primary, secondary, and tertiary alkoxyl radicals add exo-selectively to the olefinic p-bond in bicyclo[2.2.1]heptene
to afford exo-2-alkoxybicyclo[2.2.1]hept-3-yl radicals, which are trapped with BrCCl3 preferentially from the endo face to furnish
b-bromohydrine ethers in 23–67% yield.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The affinity to add to an olefinic p-bond decreases with
the steric size of an alkoxyl radical.1 Additions that oc-
cur at the lower end of the reactivity scale, however, face
severe competition from alternative processes such as
alkoxyl radical b-fragmentation (formation of carbonyl
compounds and alkyl radicals)2 or homolytic substitu-
tions. The most significant homolytic substitution
involving alkoxyl radicals in organic media is the H-
atom transfer3 from a hydrocarbon subunit of a reactant
and/or a solvent molecule, thus lowering the yield of an
O-radical addition product in a very effective manner.4
nor tert-butoxyl radical b-fragmentation are expected
to significantly interfere with C,O bond formation under
such conditions.4 To the best of our knowledge, this
concept has hitherto not been applied to prepare func-
tionalized ethers on a synthetic scale. In view of this
background, it was the aim of the present study to ex-
plore the scope of intermolecular alkoxyl radical addi-
tions to olefins using BrCCl3 as the terminal trapping
reagent. In view of the propensity, particularly, of the
tert-butoxyl radical to abstract allylic H-atoms,1,4 we
restricted ourselves to the use of bicyclo[2.2.1]heptene
(1) as substrate. The major finding of the present study
states that the synthesis of norbornene-derived b-
bromohydrine ethers under such conditions is feasible,
even in a stereoselective manner. The yield of addition
product gradually increases along the series of alk-
oxyl radical substituents C(CH3)3 < ClC6H4(CH3)2C ꢁ
C6H5(CH3)2C < CH(CH3)2 < CH3.
According to a recent interpretation of selectivity data
in intramolecular reactions, alkoxyl radicals add under
kinetic control to alkyl-substituted p-bonds.5 If the same
guideline applied for the intermolecular version, yields
of addition products should be predictable by consider-
ing rate constants and reactant concentrations associ-
ated with the major competing elementary reactions,
that is, the addition and the H-atom abstraction, since
the latter proceeds irreversibly as well.4 The tert-butoxyl
radical thus is expected to add to bicyclo[2.2.1]heptene
(1) [kadd = 1.09 · 106 Mꢀ1 sꢀ1 (300 K)]6 in synthetically
useful yields, in a ꢁ3 M solution of the olefin in a poorly
H-atom delivering solvent, for instance, benzene or
a,a,a-trifluorotoluene (TFT).7 Neither H-atom transfer
N-(Alkoxy)-5-(p-methoxyphenyl)-4-methylthiazole-2(3H)-
thiones 2a–c (Fig. 1), precursors for the generation of
the corresponding alkoxyl radicals (not shown) in pho-
tochemically or thermally induced transformations,
were prepared as reported previously.8 Pale yellow crys-
talline N-(cumyloxy)thiazolethione 2d (15%) and N-(p-
chlorophenyl) derivative 2e (13%) were synthesized by
adapting published procedures.8,9
Keywords: Alkoxyl radical; Homolytic bromination; Intermolecular
addition; Stereoselective synthesis; Tertiary thiohydroxamic acid
O-esters.
Satisfactory analytical data were obtained for all new compounds
prepared in this study.
*
Corresponding author. E-mail: hartung@chemie.uni-kl.de
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.103

6028
J. Hartung et al. / Tetrahedron Letters 48 (2007) 6027–6030
outlined above to transformations starting from second-
ary and tertiary N-alkoxythiazolethiones 2b–e provided
the derived target compounds 3b–e. The hitherto best
yields of b-bromohydrine ethers 3b–e gradually in-
creased along the series of substituents R = C(CH3)3
(23%) via ClC6H4(CH3)2C (44%), C6H5(CH3)2C (46%),
to CH(CH3)2 (51%) (Table 1, entries 4, 7, 11,
and 13).
The data obtained in the present study (Table 1) point to
an increased efficiency of b-bromohydrine ether synthe-
sis from thiazolethiones 2a–c using conventional ther-
mal conditions (conductive heating) instead of the
activation of these radical precursors in a monomode
microwave instrument– or a Rayonetꢂ chamber photo-
reactor equipped with 350 nm light bulbs (Table 1,
entries 1–9). In photochemically-induced transforma-
tions, solutions of 2b and 2c in BrCCl3, TFT, and olefin
1 gradually darkened. This observation was related to
extended reaction times and less chemoselective trans-
formations observed for those reactions. For N-cumyl-
oxy derivatives 2d (Table 1, entry 11) and 2e (Table 1,
entry 13), photoexcitation in turn was the most efficient
means of alkoxyl radical generation. This finding was
correlated with the restricted thermal stability of com-
pounds 2d–e at elevated temperatures. If heated, for
example, in a solution of BrCCl3 and TFT under micro-
wave conditions (150 ꢁC), N-(cumyloxy)thiazolethione
2d decomposes to furnish bromomethane (5),10 aceto-
phenone (6) (30%), 2-phenylpropan-2-ol (7) (20%),
a-methylstyrene (8) (31%), 2-trichloromethylsulfanyl-
thiazole 9 (23%), and 1,10-bis[5-(p-methoxyphenyl)-4-
methylthiaz-2-yl]disulfane (10) (19%). Formation of
olefin 8 is expected to occur in a Tschugaeff-type elimi-
nation, which has hitherto not been reported for tertiary
N-(alkoxy)thiazolethiones.8 The origin of the remaining
products (Scheme 1) is explicable on the basis of a well
established chain mechanism using the selected type of
alkoxyl radical precursor (Scheme 2).4,11
Figure 1. Indexing of major reactants of the present study. An = p-
(H3CO)C6H4.
Thermal activation (80 ꢁC) of N-(methoxy)thiazole-
thione 2a (c0 = 2.7 · 10ꢀ2 M) in the presence of
bicyclo[2.2.1]heptene (1) (c0 = 2.7 M), BrCCl3 (c0 =
2.7 · 10ꢀ1 M), and AIBN in C6H6 afforded 67% of 2-
exo-3-bromobicyclo[2.2.1]hept-2-yl methyl ether (3a).
Ratio and concentration of reactants, as well as further
reaction parameters, were established in an independent
study (not shown), which in turn was based on the theo-
retical considerations outlined above. Quantification of
volatile compound 3a was attainable by GC (3-exo:
3-endo = 28:72; Table 1, entry 1).à Its structure was ver-
ified after purification (column chromatography) by
1
one- and two-dimensional H and 13C NMR methods,
including NOESY measurements. Adapting conditions
à A solution of
1 (51.0 mmol), N-(cumyloxy)thiazolethione 2d
(510 lmol), and BrCCl3 (5.10 mmol) in a,a,a-trifluorotoluene
(18.5 ml) was photolyzed for 40 min at room temperature in a
Rayonetꢂ photoreactor (k = 350 nm). The reaction mixture was
concentrated under reduced pressure and purified by column chro-
matography (SiO2). For a mixture of 2-isomers of 2-bromo-3exo-(2-
phenylprop-2-yloxy)bicyclo[2.2.1]heptane (3d): MS (70 eV, EI): m/z
(%) = 229 (7) [C16H21O]+, 175 (3) [C7H1081Br]+, 173 (3) [C7H1079Br]+,
120 (45) [C8H8O]+, 119 (100) [C9H11]+, 103 (10) [C8H8]+, 91 (64)
[C7H7]+. 2-endo-Bromo-3-exo-(2-phenylprop-2-yloxy)bicyclo[2.2.1]-
heptane 2-exo-3-endo-(3d): Rf = 0.47 [pentane/Et2O = 20:1 (v/v)];
1H NMR (CDCl3, 400 MHz): d = 0.93–0.99 (m, 1H, 5-H), 1.31–
1.34 (m, 1H, 7-H), 1.36–1.49 (m, 2H, 5-H and 6-H), 1.54 (s, 3H, CH3),
1.59 (s, 3H, CH3), 1.73–1.83 (m, 2H, 6-H and 7-H), 2.06 (mc, 1H, 4-
H), 2.39 (mc, 1H, 1-H), 3.22 (t, J = 1.9 Hz, 1H, 3-H), 4.01 (mc, 1H, 2-
H), 7.23–7.27 (m, 1H, , Ar–H), 7.32–7.36 (m, 2H, Ar–H), 7.45–7.46
(m, 2H, Ar–H); 13C NMR (150 MHz, CDCl3): d = 24.0, 24.6, 29.1,
29.6, 34.5, 42.8, 44.2, 63.1, 77.3, 84.4, 126.1, 126.9, 128.1, 146.6. 2-
exo-Bomo-3-exo-(2-phenylprop-2-yloxy)-bicyclo[2.2.1]heptane 2-exo-
Alkoxyl radical addition occurred in all instances exclu-
sively (1H NMR) from the exo face of olefin 1. This
selectivity is explicable by considering steric effects and
stereoelectronic requirements associated with the C,O-
bond formation.12 An approximate orthogonal
approach of the radical onto to the HOMO of olefin 1
(not shown) is considered to be sterically less demand-
ing for the exo than for the endo mode of addition.
The selectivity of the bromination step probably origi-
nates from 1,2-induction due to steric repulsion between
the exo-oriented alkoxy substituent in, for example,
adduct 11 (Scheme 2) and BrCCl3, thus favoring
heteroatom transfer from the sterically least encroached
side.
1
3-exo-(3d): Rf = 0.46 [pentane/Et2O = 20:1 (v/v)]; H NMR (CDCl3,
400 MHz): d = 0.85–0.92 (m, 1H, 5-H), 0.99–1.06 (m, 1H, 6-H), 1.12–
1.15 (mc, 1H, 7-H), 1.32–1.41 (mc, 1H, 5-H), 1.47–1.53 (m, 1H, 6-H),
1.58 (s, 3H, CH3), 1.59 (s, 3H, CH3), 2.06 (mc, 1H, 7-H), 2.14 (mc, 1H,
3
1-H), 2.48 (mc, 1H, 4-H), 3.11 (mc, 1H, 3-H), 3.93 (dd, 1H, J = 6.4,
– Discover instrument (CEM) [300 W, 80 ml quartz glass vessel
equipped with a 20 bar excess pressure valve, stirring device, cooling
fan, temperature measurement via IR sensor; mode: power time;
pmax = 10 bar]. It is for safety reasons highly recommended to adhere
to the precautions outlined in Ref. 8.
1.9 Hz, 2-H), 7.23–7.26 (m, 1H, , Ar–H), 7.32–7.36 (m, 2H, Ar–H),
7.52–7.55 (m, 2H, Ar–H); 13C NMR (150 MHz, CDCl3): d = 25.5,
27.0, 28.7 (2 · C), 33.6, 44.2, 46.5, 61.6, 76.5, 78.6, 126.4, 126.8, 128.0,
147.0.

J. Hartung et al. / Tetrahedron Letters 48 (2007) 6027–6030
6029
Table 1. Formation of b-bromohydrine ethers 3 from N-(alkoxy)thiazolethiones 2, BrCCl3 and bicyclo[2.2.1]heptene (1)
Entry
2
Conditions
Solvent
3 [% from 2]
3 3-exo:3-endo
4 [% from BrCCl3]
4 3-exo:3-endo
1
2
3
4
5
6
7
8
2a
2a
2a
2b
2b
2b
2c
2c
2c
2d
2d
2e
2e
DT (80 ꢁC)/AIBN
MW (150 ꢁC)
hm (20 ꢁC)
DT (80 ꢁC)/AIBN
MW (150 ꢁC)
hm (20 ꢁC)
DT (80 ꢁC)/AIBN
MW (150 ꢁC)
hm (20 ꢁC)
MW (150 ꢁC)
hm (20 ꢁC)
C6H6
67
50
17
51
33
26
23
11
20
3d
46
3e
28:72a
26:74
27:73
24:76b
25:75
23:77
14:86c
28:72
20:80
26:74
24:76
26:74
22:78
67
77
92
66
80
93
76
88
90
84
92
85
93
7:93
9:91
12:88
7:93
9:91
11:89
7:93
9:91
7:93
20:80
7:93
20:80
7:93
C6H5CF3
C6H5CF3
C6H6
C6H5CF3
C6H5CF3
C6H6
C6H5CF3
C6H5CF3
C6H5CF3
C6H5CF3
C6H5CF3
C6H5CF3
9
10
11
12
13
MW (150 ꢁC)
hm (20 ꢁC)
44
MW: monomode microwave instrument; hm: Rayonetꢂ chamber photoreactor equipped with 350 nm light bulbs. Speciation of products not
mentioned in Table 1: 2-methyl-2-(2-exo-3-endo-3-bromobicyclo[2.2.1]hept-2-yl)propannitrile (3%a, 2%b,c), acetophenone (6) (55%),d 1-methyl-1-
phenylethan-1-ol (7) (22%),d a-methylstyrene (8) (3%),d a-methyl-(p-chlorophenyl)styrene (28%),e 2-(p-chlorophenyl)propan-2-ol (35%),e methyl-
(p-chlorophenyl)ketone (30%)e.
Scheme 1. Products formed from thermal decomposition of N-(cumyloxy)thiazolethione 2d in the presence of BrCCl3 in a monomode microwave
c
instrument (300 W, 150 ꢁC). aGC–MS, bquantitative GC analysis, purification via column chromatography.
The synthesis of b-bromohydrine ethers 3 in the present
investigation was consistently paralleled by formation of
the BrCCl3-addition product 4.13 This result shows that
the thiocarbonyl group in thione 2 is one but probably
not the most effective functionality for trapping chain
bicyclo[2.2.1]heptene (1) has been successfully demon-
strated. Although some of the yields remained at the
moderate level, we wish to point out that the synthesis
of derivatives of 3, which have attracted the attention
as, for example, pesticides14 and pharmacological active
compounds,15 is in several instances difficult to achieve
using ionic transformations.16,17 We are well aware of
the beneficial reactivity of bicyclo[2.2.1]heptene (1) for
the present investigation, in particular due to its reluc-
tance to undergo allylic H-atom abstraction. The aim
to broaden the scope of the alkoxyl radical method by
varying the type of olefin used as a radical acceptor is
being extensively pursued in this laboratory at the
moment.
Å
carrying CCl3 radicals.13 Support for this argumenta-
tion comes from an experiment that was conducted by
heating (80 ꢁC) olefin 1, BrCCl3, and AIBN in a solution
of C6H6 in the absence of 2. The reaction provides 38%
of
3-bromo-2-exo-(trichloromethyl)bicyclo[2.2.1]hep-
tane 4 in a 3-exo:3-endo ratio of 7:93.
In conclusion, the feasibility of b-bromohydrine ether
synthesis via intermolecular alkoxyl radical addition to

6030
J. Hartung et al. / Tetrahedron Letters 48 (2007) 6027–6030
2. Avila, D. V.; Brown, C. E.; Ingold, K. U.; Lusztyk, J. J.
Am. Chem. Soc. 1993, 115, 466–470.
3. Sway, M. I. J. Chem. Soc., Faraday Trans. 1991, 2157–
2159.
ˇ
4. Hartung, J.; Gottwald, T.; Spehar, K. Synthesis 2002,
1469–1498.
5. Hartung, J.; Daniel, K.; Rummey, C.; Bringmann, G. Org.
Biomol. Chem. 2006, 4, 4089–4100.
6. Wong, P. C.; Griller, D.; Scaiano, J. C. J. Am. Chem. Soc.
1982, 104, 5106–5108.
7. Maul, J. J.; Ostrowski, P. J.; Ublacker, G. A.; Linclau, B.;
Curran, D. P. In Modern Solvents in Organic Synthesis;
Knochel, P., Ed.; Springer: Berlin, 1999; Vol. 206, pp 78–
105.
8. Hartung, J.; Daniel, K.; Gottwald, T.; Groß, A.; Schnei-
ders, N. Org. Biomol. Chem. 2006, 4, 2313–2322.
9. Hartung, J.; Schneiders, N.; Bergstra¨ßer, U. Acta Crys-
tallogr., Sect. E 2006, 62, o4713–o4714.
10. Archbold, M. E.; Redeker, K. R.; Davis, S.; Elliot, T.;
Kalin, R. M. Rapid Commun. Mass Spectrom. 2005, 19,
337–342.
Scheme 2. Formation of b-bromohydrine ether 2-exo-3-endo-3d as
major product from N-(cumyloxy)thiazolethione 2d, norbornene 1 and
BrCCl3 in a radical chain reaction (R = 2-phenylprop-2-yl).
ˇ
11. Hartung, J.; Kneuer, R.; Laug, S.; Schmidt, P.; Spehar,
K.; Svoboda, I.; Fuess, H. Eur. J. Org. Chem. 2003, 4033–
4052.
12. Hartung, J.; Kneuer, R.; Rummey, C.; Bringmann, G.
J. Am. Chem. Soc. 2004, 126, 12121–12129.
13. (a) Ludwick, A. G.; Martin, J. C. J. Org. Chem. 1969, 34,
4108–4115; (b) Barstow, L. E.; Wiley, G. A. Tetrahedron
Lett. 1968, 9, 865–868; (c) Kharasch, M. S.; Friedlander,
H. N. J. Org. Chem. 1949, 14, 239–244.
Acknowledgments
This work was generously supported by the Deutsche
Forschungsgemeinschaft (Grant Ha1705/5–2). Also,
we wish to express our gratitude to Dipl. Chem. Annem-
arie Heydt for performing head-space GC–MS analysis
of bromomethane.
14. Buchbauer, G.; Weck, A. M. Chem. Ztg. 1985, 109, 255–
265.
15. Krieger, H. Arzneimittel Forsch. 1968, 18, 129–134.
16. Dalton, D. R.; Rodebaugh, R. K.; Jefford, C. W. J. Org.
Chem. 1972, 37, 362–367.
References and notes
17. Fujioka, H.; Fujita, T.; Kotoku, N.; Ohba, Y.; Nagatomi,
Y.; Hiramatsu, A.; Kita, Y. Chem. Eur. J. 2004, 10, 5386–
5397.
1. Elson, I. H.; Mao, S. W.; Kochi, J. K. J. Am. Chem. Soc.
1975, 97, 335–341.